Bicyclic and tricyclic hetroaromatic compounds

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     and the pharmaceutically acceptable salts thereof, wherein W, Q, X, X 1 , Y and Z are as defined herein. These compounds bind with high selectivity and/or high affinity to the benzodiazepine site of GABA A  receptors and are therefore useful in the treatment of central nervous system (CNS) diseases and as probes for the localization of GABA A  receptors in tissue samples. Also disclosed are intermediates useful in the preparation of these compounds.

FIELD OF THE INVENTION

[0001] This invention relates to heterocyclic derivatives that bind tothe benzodiazepine site of GABA_(A) receptors. This invention alsorelates to pharmaceutical compositions comprising such compounds and tothe use of such compounds in the treatment of central nervous system(CNS) diseases. This invention also relates to the use of theseheterocyclic compounds in combination with one or more other CNS agentsto potentiate the effects of the other CNS agents. Additionally thisinvention relates to the use such compounds as probes for thelocalization of GABA_(A) receptors in tissue sections.

BACKGROUND

[0002] The GABA_(A) receptor superfamily represents one of the classesof receptors through which the major inhibitory neurotransmitter,γ-aminobutyric acid, or GABA, acts. Widely, although unequally,distributed through the mammalian brain, GABA mediates many of itsactions through a complex of proteins called the GABA_(A) receptor,which causes alteration in chloride conductance and membranepolarization.

[0003] A number of cDNAs for GABA_(A) receptor subunits have beencharacterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits havebeen identified. It is generally accepted that native GABA_(A) receptorsare typically composed of 2α, 2β, and 1γ subunits (Pritchett & SeeburgScience 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998;6:1-18). Evidence such as message distribution, genome localization andbiochemical study results suggest that the major naturally occurringreceptor combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂ (Mohler et.al. Neuroch. Res. 1995; 20(5): 631-636).

[0004] Benzodiazepines exert their pharmacological actions byinteracting with the benzodiazepine binding sites associated with theGABA_(A) receptor. In addition to the benzodiazepine site, the GABA_(A)receptor contains sites of interaction for several other classes ofdrugs. These include a steroid binding site, a picrotoxin site, and thebarbiturate site. The benzodiazepine site of the GABA_(A) receptor is adistinct site on the receptor complex that does not overlap with thesite of interaction for GABA or for other classes of drugs that bind tothe receptor (see, e.g., Cooper, et al., The Biochemical Basis ofNeuropharmacology, 6^(th) ed., 1991, pp. 145-148, Oxford UniversityPress, New York). Early electrophysiological studies indicated that amajor action of the benzodiazepines was enhancement of GABAergicinhibition. Compounds that selectively bind to the benzodiazepine siteand enhance the ability of GABA to open GABA_(A) receptor channels areagonists of GABA receptors. Other compounds that interact with the samesite but negatively modulate the action of GABA are called inverseagonists. Compounds belonging to a third class bind selectively to thebenzodiazepine site and yet have little or no effect on GABA activity,but can block the action of GABA_(A) receptor agonists or inverseagonists that act at this site. These compounds are referred to asantagonists.

[0005] The important allosteric modulatory effects of drugs acting atthe benzodiazepine site were recognized early and the distribution ofactivities at different receptor subtypes has been an area of intensepharmacological discovery. Agonists that act at the benzodiazepine siteare known to exhibit anxiolytic, sedative, and hypnotic effects, whilecompounds that act as inverse agonists at this site elicit anxiogenic,cognition enhancing, and proconvulsant effects. While benzodiazepineshave a long history of pharmaceutical use as anxiolytics, thesecompounds often exhibit a number of unwanted side effects. These mayinclude cognitive impairment, sedation, ataxia, potentiation of ethanoleffects, and a tendency for tolerance and drug dependence.

[0006] GABA_(A) selective ligands may also act to potentiate the effectsof other CNS active compounds. For example, there is evidence thatselective serotonin reuptake inhibitors (SSRIs) may show greaterantidepressant activity when used in combination with GABA_(A) selectiveligands than when used alone.

SUMMARY OF THE INVENTION

[0007] This invention provides heterocyclic derivatives, particularlyimidazoquinoline and 1,2,4-triazoloquinoline derivatives, that bind tothe benzodiazepine site of the GABA_(A) receptor, including humanGABA_(A) receptors. Preferably, these compounds also bind with highaffinity to such receptors. More preferably, these compounds bind withhigh selectivity to such receptors.

[0008] The invention provides compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula 1.

[0009] The invention further provides methods of treating patientssuffering from CNS disorders with a therapeutically effective amount ofa compound of the invention. The patient may be a human or other mammal.Treatment of humans, domesticated companion animals (pets) and livestockanimals suffering from CNS disorders with a therapeutically effectiveamount of a compound of the invention is contemplated by the invention.

[0010] In a separate aspect, the invention provides a method ofpotentiating the actions of other CNS active compounds. This methodcomprises administering a therapeutically effective amount of a compoundof the invention with another CNS active compound.

[0011] Additionally this invention provides for the use of the compoundsof the invention as probes for the localization of GABA_(A) receptors intissue samples, in particular, tissue sections.

[0012] The invention also provides intermediate compounds that areuseful in the preparation of compounds of Formula 1.

[0013] A broad aspect of the invention is directed to compounds ofFormula 1:

[0014] And the pharmaceutically acceptable salts thereof, wherein:

[0015] X represents N or CR₁, wherein

[0016] R₁ is hydrogen, halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono ordi(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl;

[0017] X₁ represents N, CH, or C₁-C₆alkyl;

[0018] Y and Z are independently hydrogen, halogen, hydroxy, cyano,nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; or

[0019] Y and Z together form an arylene ring or a C₃-C₈ cycloalkylenering, each of which is optionally substituted with up to four groups R₂independently chosen at each occurrence from halogen, hydroxy, cyano,nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;

[0020] W is aryl or heteroaryl, each of which is optionally substitutedwith one or more groups R_(A), wherein each R_(A) is independently

[0021] i) halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), or —SO₂(C₁-C₈ alkyl);

[0022] ii) aryl or heteroaryl, each of which is optionally substitutedwith one or two groups independently selected from halogen, hydroxy,cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;

[0023] iii) C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl,C₃-C₈cycloalkyl(C₁-C₃ alkyl), C₃-C₈cycloalkenyl, each of which isunsubstituted or substituted by one or more substituents independentlyselected from hydroxy, oxo, halogen, C₁-C₆alkoxy, —CONH₂,—CONHC₁-C₆alkyl, —CON(C₁-C₆alkyl)(C₁-C₆alkyl), —COOH, and—CO₂C₁-C₆alkyl; or

[0024] iv) NR₄R₅, wherein R₄, R₅ and the nitrogen to which they areattached form a monocyclic or bicyclic ring optionally containing one ormore of oxo, O, S, SO, SO₂, or NR₆ wherein R₆ is hydrogen, C₁-C₆alkyl,or Ar—(C₁-C₆alkyl) where

[0025] Ar is aryl or heteroaryl, each of which is optionally substitutedby one or two groups independently selected from halogen, hydroxy,cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;and

[0026] Q is selected Formulas III, IV and V:

[0027]  wherein:

[0028] J is N or C₁-C₈ alkylene; and

[0029] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl, or Ar₁,wherein Ar₁ is aryl or heteroaryl, each of which may be substituted withone or two of R_(B), where each R_(B) independently carries thedefinition of R_(A); or

[0030] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring optionally containing one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl, or Ar₁—(C₁-C₈ alkyl); wherein Ar₁ is optionallysubstituted with one or two of R_(B), where each R_(B) independentlycarries the definition of R_(A); and wherein the monocyclic or bicyclicring is optionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0031] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0032] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0033] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring which is optionally substituted withone or more of halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkyl,C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono ordi(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; and

[0034] n is 1, 2, 3, or 4; and

[0035] W′

[0036] (i) independently carries the same definition as W;

[0037] (ii) represents —OR where R is C₁-C₈ alkyl or aryl(C₁-C₆)alkyl;or

[0038] (iii) is M₅ where M₅ is hydroxy, C₁-C₈ alkyl, aryl(C₁-C₆)alkyl or—N(C₁-C₄ alkyl)(C₁-C₄ alkoxy).

DETAILED DESCRIPTION OF THE INVENTION

[0039] For compounds of Formula I (above) preferred aryl and heteroarylgroups representing the variable W include, but are not limited to thegroups W₁ defined as follows:

[0040] W₁: phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is optionallysubstituted by one or more groups independently chosen at eachoccurrence from

[0041] halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), andphenyl.

[0042] Especially preferred groups representing the variable W includesthe groups W₂, wherein

[0043] W₂ represents phenyl, naphthyl, thienyl, benzothienyl, pyridyl,quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is optionallysubstituted by one or more groups independently chosen at eachoccurrence from

[0044] halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), andphenyl.

[0045] A preferred arylene ring formed by Y and Z is benzo. Particularlypreferred benzo rings are unsubstituted or substituted with one, two, orthree, more preferably one or two, of R₂ where each R₂ is the same as ordifferent than every other R₂. Preferred benzo substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₆ alkyl),and —N(C₁-C₆ alkyl)₂. Highly preferred benzo substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

[0046] Preferred cycloalkylene rings formed by Y and Z are 5-, 6-, and7-membered cycloalkylene rings. Particularly preferred are 5-, 6-, and7-membered cycloalkylene rings are that are unsubstituted or aresubstituted with one, two, or three, preferably one or two, of R₂ whereeach R₂ is the same as or different than every other R₂. Preferredcycloalkylene substituents are halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, —NO₂, —CN, —SO₂NH₂, amino, —NH(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)₂. Highly preferred cycloalkylene substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

[0047] A preferred group of compounds of the invention includes thoserepresented by Formula A-3

[0048] wherein R₂, Q, X₁, X and W are as defined for Formula I and R₂ isindependently chosen at each occurrence.

[0049] Preferred compounds of Formula A-3 include compounds where

[0050] W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of:

[0051] halogen, hydroxy, cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.

[0052] Even more preferred compounds of Formula A-3 include those where

[0053] R₂ is independently chosen at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0054] Q is selected from the group consisting of Formulas III, IV andV:

[0055] J is N or C₁-C₈ alkylene; and

[0056] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0057] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0058] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0059] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0060] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0061] n is 1, 2, 3, or 4;

[0062] W′ phenyl, pyridyl, or naphthyl; and

[0063] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0064] Other preferred compounds of Formula A-3 include compounds whereX₁ is CR₁ and R₁ is hydrogen or C₁-C₆alkyl.

[0065] Preferred compounds of Formula A-3 also include compounds whereinX₁ is CR₁ and R₁ is hydrogen or C₁-C₆alkyl, and W has the definition ofW₁ or more preferably W has the definition of W₂.

[0066] Also preferred are compounds of Formula A-3 wherein X₁ is

[0067] CR₁ and R₁ is hydrogen or C₁-C₆alkyl;

[0068] R₂ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0069] Q is selected from the group consisting of Formulas III, IV and V

[0070]  wherein:

[0071] J is N or C₁-C₈ alkylene; and

[0072] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0073] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0074] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0075] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0076] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0077] n is 1, 2, 3, or 4;

[0078] W′ phenyl, pyridyl, or naphthyl; and

[0079] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0080] Preferred W groups of Formula A-3 are those carrying k-2substituents where k is the number of hydrogen atoms on the aryl orheteroaryl group defined by W. More preferably, the W groups carry k-3substituents. The most preferred W groups are those carrying 1 or 2substituents, and those substituents are most preferably hydroxy,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy,amino or mono- or di(C₁-C₆)alkylamino.

[0081] Another preferred group of compounds of the invention are thosedepicted by Formula A-6

[0082] wherein R₂, Q, and X are defined as in Formula I, R₂ isindependently defined at each occurrence, and W is W₁.

[0083] More preferred are compounds of Formula A-6 are those where R₂,Q, and X are defined as in Formula I, and W is W₂.

[0084] More preferred are compounds of Formula A-6 include those where

[0085] R₂ are independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0086] Q is selected from the group consisting of Formulas III, IV andV:

[0087]  wherein:

[0088] J is N or C₁-C₈ alkylene; and

[0089] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0090] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0091] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0092] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0093] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0094] n is 1, 2, 3, or 4;

[0095] W′ phenyl, pyridyl, or naphthyl; and

[0096] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0097] Preferred W groups of Formula A-6 are those carrying k-2substituents where k is the number of hydrogen atoms on the aryl orheteroaryl group defined by W. More preferably, the W groups carry k-3substituents. The most preferred W groups are those carrying 1 or 2substituents, and those substituents are most preferably hydroxy,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy,amino or mono- or di(C₁-C₆)alkylamino.

[0098] Another preferred group of compounds of the invention isrepresented by Formula A-9, i.e., compound where both X and X₁ are bothCH,

[0099] wherein R₁, R₂, and Q are as defined as in Formula 1, and W isW₁.

[0100] More preferred are compounds of Formula A-9 include those whereinR₂ and Q are as defined in Formula I, and W is W₁.

[0101] Most preferred compounds of formula A-9 are those wherein

[0102] R₂ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0103] Q is selected from the group consisting of Formulas III, IV and

[0104] J is N or C₁-C₈ alkylene; and

[0105] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0106] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0107] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0108] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0109] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0110] n is 1, 2, 3, or 4;

[0111] W′ phenyl, pyridyl, or naphthyl; and

[0112] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0113] Preferred W groups of Formula A-9 are those carrying k-2substituents where k is the number of hydrogen atoms on the aryl orheteroaryl group defined by W. More preferably, the W groups carry k-3substituents. The most preferred W groups are those carrying 1 or 2substituents, and those substituents are most preferably hydroxy,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy,amino or mono- or di(C₁-C₆)alkylamino.

[0114] Still another preferred group of compounds is represented byFormula A-12.

[0115] wherein

[0116] wherein R₁, Q, and X are as defined in Formula I and

[0117] p is 1, 2, 3, and 4; and W is W₁.

[0118] More preferred compounds of Formula A-12 are those where

[0119] R₂, Q, and X are as defined in Formula 1;

[0120] p is 1, 2, 3, or 4; and

[0121] W is W₂.

[0122] Even more preferred compounds of Formula 12 are those wherein

[0123] R₂ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;

[0124] Q is selected from the group consisting of Formulas III, IV andV:

[0125] wherein:

[0126] J is N or C₁-C₈ alkylene; and

[0127] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0128] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0129] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0130] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0131] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0132] n is 1, 2, 3, or 4;

[0133] W′ phenyl, pyridyl, or naphthyl; and

[0134] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0135] Preferred compounds of the invention are also encompassed byFormula A-15

[0136] wherein R₁, Q, and X are as defined in Formula 1; p is 1, 2, 3,or 4; and W is W₁.

[0137] More compounds of Formula A-15 are those wherein

[0138] R₂, Q, and X are as defined in Formula 1;

[0139] p is 1, 2, or 3; and

[0140] W is W₂.

[0141] Even more preferred compounds of Formula A-15 are those where

[0142] R₂ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0143] Q is selected from the group consisting of Formulas III, IV andV:

[0144] wherein:

[0145] J is N or C₁-C₈ alkylene; and

[0146] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0147] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0148] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0149] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0150] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0151] n is 1, 2, 3, or 4;

[0152] W′ phenyl, pyridyl, or naphthyl; and

[0153] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0154] Preferred compounds of the invention are also encompassed byFormula A-17, i.e., compounds where Y and Z are not joined to form anaryl ring.

[0155] wherein X, X₁, and Q are defined as in Formula I, and W is W₁;and

[0156] Y and Z are independently selected from hydrogen, halogen,hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl.

[0157] More preferred compounds of Formula A-17 are those wherein

[0158] X, X₁, and Q are defined as in Formula I, and W is W₂; and

[0159] Y and Z are independently selected from hydrogen, halogen,hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl.

[0160] Even more preferred are compounds of Formula A-17 wherein

[0161] X is N or CH; and

[0162] Q is selected from the group consisting of Formulas III, IV andV:

[0163] wherein:

[0164] J is N or C₁-C₈ alkylene; and

[0165] R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0166] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0167] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0168] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0169] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0170] n is 1, 2, 3, or 4;

[0171] W′ phenyl, pyridyl, or naphthyl; and

[0172] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0173] Other preferred compounds are represented by Formula A-18

[0174] W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each ofwhich is optionally substituted with one, two, or three of V₁, V₂ andV₃, where V₁, V₂, and V₃ independently represent

[0175] halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino,—NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl);

[0176] R₁ and R₂ independently represent hydrogen, halogen, hydroxy,C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or—N(C₁-C₈ alkyl)(C₁-C₈ alkyl);

[0177] X is nitrogen or CR₁₁₁, where R₁₁₁ is hydrogen, halogen, hydroxy,C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or—N(C₁-C₈ alkyl)(C₁-C₈ alkyl); and

[0178] R₉ and R₁₀ are independently hydrogen or C₁-C₈ alkyl; or

[0179] NR₉R₁₀ represents a 5- to 7-membered ring optionally containingone or two double bonds, O and/or N—R₈ where R₈ is hydrogen, C₁-C₈alkyl, or HAr—(C₁-C₈)alkyl, where HAr is phenyl, pyridinyl, orpyrimidinyl, each of which is optionally substituted with one or twohalogen, hydroxy, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂,—CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl).

[0180] More preferred compounds of Formula A-18 include those where X isnitrogen.

[0181] Still other more preferred compounds of Formula A-18 are thosewhere X is CH or a carbon atom substituted with (C₁-C₆) alkyl.

[0182] Other preferred compounds are represented by Formula A-19

[0183] W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each ofwhich is optionally substituted with one, two, or three of V₁, V₂ andV₃, where V₁, V₂, and V₃ independently represent

[0184] halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino,—NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl);

[0185] R₁ and R₂ independently represent hydrogen, halogen, hydroxy,C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or—N(C₁-C₈ alkyl)(C₁-C₈ alkyl);

[0186] X is nitrogen or CR₁₁₁, where R₁₁₁ is hydrogen, halogen, hydroxy,C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or—N(C₁-C₈ alkyl)(C₁-C₈ alkyl); and

[0187] W′ represents

[0188] (i) phenyl optionally substituted with one, two, or three of T₁,T₂ and T₃, where T₁, T₂, and T₃ independently represent halogen,hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl),or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl);

[0189] (ii) —OR where R is C₁-C₈ alkyl or aryl(C₁-C₆)alkyl; or

[0190] (iii) M₅ where M₅ is hydroxy, C₁-C₈ alkyl, aryl(C₁-C₆)alkyl or—N(C₁-C₄ alkyl)(C₁-C₄ alkoxy).

[0191] More preferred compounds of Formula A-19 include those where X isnitrogen.

[0192] Still other more preferred compounds of Formula A-19 are thosewhere X is CH or a carbon atom substituted with (C₁-C₆) alkyl.

[0193] Still other preferred compounds are represented by Formula A-20

[0194] wherein and Q are as defined in Formula I, and W is W₁; and

[0195] Y and Z are independently selected from hydrogen, halogen,hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl.

[0196] Especially preferred definitions of Y and Z for Formula A-20, arehydrogen, halogen, and C₁-C₆alkyl. More preferred compounds of FormulaA-20, are those where W is W₂.

[0197] Particularly preferred compounds of Formula A-20 are thosewherein

[0198] Y and Z are independently chosen from hydrogen, halogen, andC₁-C₆alkyl, W is W₂; and

[0199] Q is selected from the group consisting of Formulas III, IV andV:

[0200] wherein:

[0201] J is N or C₁-C₈ alkylene; and

[0202] R₉, and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or

[0203] R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;

[0204] R₁₁ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and

[0205] R₁₂ is selected from the group consisting of hydrogen, C₁-C₈alkyl, and C₁-C₈ alkoxy; or

[0206] R₁₁ and R₁₂ together with the atoms to which they are attachedform a 5-8 membered monocyclic ring, which is optionally substitutedwith C₁-C₆alkyl; and

[0207] n is 1, 2, 3, or 4;

[0208] W′ phenyl, pyridyl, or naphthyl; and

[0209] W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

[0210] For Formulas III, IV, and V

[0211] Preferred R₈ substituents on the hetero nitrogen (which issometime present in the 4- to 8-membered monocyclic or bicyclic ringformed by R₉ and R₁₀) are methyl, ethyl, n-propyl and isopropyl.

[0212] Preferred JR₉R₁₀ groups include 1-piperidinyl optionally mono- ordisubstituted with C₁-C₆ alkyl, preferably methyl or ethyl;1-piperazinyl optionally mono- or disubstituted with C₁-C₆ alkyl,preferably methyl or ethyl; and morpholinyl optionally mono- ordisubstituted with C₁-C₆ alkyl, preferably methyl or ethyl. Otherpreferred JR₉R₁₀ groups include pyrrolyl and imidazolinyl, each of whichis optionally mono- or disubstituted with C₁-C₃ alkyl or hydroxy (C₁-C₆)alkyl, and preferably monosubstituted with methyl, ethyl, orhydroxymethyl.

[0213] Where the nature of the substituents permits, the groupsrepresented by JR₉R₁₀ encompass various stereoisomers. While theinvention encompasses racemic mixtures and mixtures of enantiomers inwhich one enantiomer is present in an enantiomeric excess, the preferredcompounds of the invention are those where only a single, at leastrelatively pure, stereoisomer is present. Examples of preferred JR₉R₁₀stereoisomers include the following:

[0214] As used herein, monocyclic and bicyclic rings include bothcarbocyclic rings where J is, e.g., CH, and, for those rings formed byNR₄R₅ and NR₉R₁₀, nitrogen-containing carbocyclic ring systems of thetype having at least one nitrogen, e.g., the nitrogen in NR₄R₅. Thus, inNR₄R₅ and NR₉R₁₀, the R₄R₅ and R₉R₁₀ groups together represent, forexample, a C₄-C₆ straight chain alkylene group which together with thenitrogen atom to which, e.g., R₉ and R₁₀ are attached form a 5- to7-membered ring system. This ring system may be further substitutedwith, e.g., C₁-C₆ alkyl or may contain one or two double bonds, O,and/or a substituted nitrogen as defined herein. In situations where Jis, for example, CH, the resulting ring can contain hetero atoms such asoxygen or nitrogen giving rise to, e.g., a 4-piperidinyl group.

[0215] When J is a C₁-C₈ alkylene group, that group is attached at oneterminus to the parent carbonyl and the groups R₉ and R₁₀ are attachedat any position along the alkylene chain. For example, JR₉R₁₀ representsgroups such as neopentyl, t-butyl, isopropyl, 2-ethylhexyl and n-octyl.Further, R₉R₁₀ may represent an alkylene group, e.g., a C₅ alkylenegroup attached to the terminus of J where is n-propyl giving rise to acyclohexylpropyl group.

[0216] Particularly preferred compounds of Formulas A-3, A-6, and A-9,A-12, A-15, A-17, and A-20 are those where Q represents either FormulaIII or Formula IV. In highly preferred embodiments, Q represents FormulaIII where

[0217] R₉, R₁₀ and the nitrogen atom to which they are attachedrepresent mono- or di(C₁-C₆)alkylamino; or

[0218] R₉, R₁₀ and the nitrogen to which they are attached form a 5- or6-membered ring.

[0219] The 5- and 6-membered rings are optionally substituted with C₁-C₆alkyl or hydroxy(C₁-C₆)alkyl, preferably hydroxymethyl, and optionallycontain one hetero atom selected from oxygen, sulfur, or nitrogen. Thehetero sulfur atom may be oxidized to a sulfone or sulfoxide. The heteronitrogen is optionally substituted with R₈ where R₈ represents hydrogenor C₁-C₈ alkyl.

[0220] Other particularly preferred compounds of the invention are thosewhere W represents optionally substituted phenyl, isoxazolyl, orthienyl. Highly preferred compounds are those where the phenyl isunsubstituted or substituted with one or two of halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, or hydroxy. Otherhighly preferred compounds are those where W is isoxazolyl optionallysubstituted with C₁-C₆ alkyl, most preferably methyl, C₁-C₆ alkoxy, orhalogen. The most preferred compounds are those where W is phenyloptionally substituted with one halogen, preferably chloro or fluoro, orone hydroxy. Even more preferably, the halogen or hydroxy group is inthe ortho or para position of the phenyl ring.

[0221] The invention also provides intermediates of Formula A-69

[0222] wherein Y, Z, and X₁ are defined as for Formula I, R isC₁-C₆alkyl, and R_(N) is hydrogen, C₁-C₆ alkyl, or —C(O)W where W is asdefined for Formula I.

[0223] Preferred intermediate compounds can be represented by FormulaA-70

[0224] wherein X₁ and R₂ are as defined for Formula I, and R and R_(N)are as defined in Formula A-69.

[0225] Another preferred class of intermediates is represented byFormula A-71

[0226] wherein X₁, Y, and Z are defined as in Formula I, R isC₁-C-₆alkyl and

[0227] W is phenyl, pyridyl, isoxazolyl, or thienyl, each of which isunsubstituted or substituted with one or more of halogen, hydroxy,cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂,—CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl),—S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.

[0228] More preferred are intermediate compounds of Formula A-72

[0229] wherein X₁ and R₂ are as defined in Formula I, R is C₁-C₆alkyl,and W represents W₂.

[0230] Even more preferred are intermediates of Formula A-73 wherein

[0231] R₂, is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0232] W is W₂; and

[0233] X₁ is N or CH.

[0234] Another group of intermediate compounds useful in preparingcompounds of the instant invention are those of Formula A-74

[0235] wherein Y, Z, X₁, and W are as defined for Formula I, and R isC₁-C₆ alkyl.

[0236] More preferred intermediate compounds are represented by formulaA-75

[0237] wherein X and R₂ are as defined in Formula I, R₂ is independentlychosen at each occurrence, W is W₂, and R is C₁-C₆alkyl.

[0238] Even more preferred are intermediates of Formula A-75 wherein

[0239] R₂ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0240] W is W₂; and

[0241] X is N or CR₁; wherein R₁ is selected from the group consistingof hydrogen, halogen, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

[0242] Still another group of intermediates that are useful in preparingcompounds of the instant invention are those of Formula A-76

[0243] wherein Y, Z, X, X₁, and W are as defined for Formula I, and M₅is hydroxy, C₁-C₈alkyl, aryl(C₁-C₆)alkyl, or—N(C₁-C₄alkyl)(C₁-C₄alkoxy).

[0244] A more preferred group of intermediates of Formula A-76 are thoseof Formula A-77

[0245] wherein X₁, R₂ and M₅ are as defined in claim 76; and

[0246] W is W₂.

[0247] A preferred group of intermediates of Formula A-77 are thosewherein

[0248] R₂ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy;

[0249] W is W₂; and

[0250] X₁ is N or CH.

[0251] This invention relates to imidazoquinoline and triazoloquinolinederivatives and related compounds, preferred examples of which bind withhigh affinity to the benzodiazepine site of GABA_(A) receptors,including human GABA_(A) receptors. Preferred fused aryl substitutedtetrahydroindazoles and related compounds that bind with highselectivity to the benzodiazepine site of GABA_(A) receptors, includinghuman GABA_(A) receptors, are also included in this invention. Withoutwishing to be bound to any particular theory, it is believed that theinteraction of the compounds of Formula I with the benzodiazepine siteresults in the pharmaceutical utility of these compounds.

[0252] The invention further comprises methods of treating patients inneed of such treatment with an amount of a compound of the inventionsufficient to alter the symptoms of a CNS disorder. Compounds of theinventions that act as agonists at ₂β₃γ₂ and ₃β₃γ₂ receptor subtypes areuseful in treating anxiety disorders such as panic disorder, obsessivecompulsive disorder and generalized anxiety disorder; stress disordersincluding post-traumatic stress, and acute stress disorders. Compoundsof the inventions that act as agonists at ₂β₃γ₂ and ₃β₃β₂ receptorsubtypes are also useful in treating depressive or bipolar disorders andin treating sleep disorders. Compounds of the invention that act asinverse agonists at the ₅β₃γ₂ receptor subtype or ₁β₂γ₂ and ₅β₃γ₂receptor subtypes are useful in treating cognitive disorders includingthose resulting from Down Syndrome, neurodegenerative diseases such asAlzheimer's disease and Parkinson's disease, and stroke relateddementia. Compounds of the invention that act as agonists at the ₁β₂γ₂receptor subtype are useful in treating convulsive disorders such asepilepsy. Compounds that act as antagonists at the benzodiazepine siteare useful in reversing the effect of benzodiazepine overdose and intreating drug and alcohol addiction.

[0253] The diseases and/or disorders that can also be treated usingcompounds and compositions according to the invention include:

[0254] Depression, e.g. depression, a typical depression, bipolardisorder, depressed phase of bipolar disorder.

[0255] Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panicdisorder+/−agoraphobia, social phobia, specific phobia, Post traumaticstress disorder, obsessive compulsive disorder (OCD), dysthymia,adjustment disorders with disturbance of mood and anxiety, separationanxiety disorder, anticipatory anxiety acute stress disorder, adjustmentdisorders, cyclothymia.

[0256] Sleep disorders, e.g. sleep disorders including primary insomnia,circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, includingnightmare disorder, sleep terror disorder, sleep disorders secondary todepression and/or anxiety or other mental disorders, substance inducedsleep disorder.

[0257] Cognition Impairment, e.g. cognition impairment, Alzheimer'sdisease, Parkinson's disease, mild cognitive impairment (MCI),age-related cognitive decline (ARCD), stroke, traumatic brain injury,AIDS associated dementia, and dementia associated with depression,anxiety or psychosis.

[0258] Attention Deficit Disorder, e.g. attention deficit disorder(ADD), and attention deficit and hyperactivity disorder (ADHD).

[0259] The invention also provides pharmaceutical compositionscomprising compounds of the invention, including packaged pharmaceuticalcompositions for treating disorders responsive to GABA_(A) receptormodulation, e.g., treatment of anxiety, depression, sleep disorders orcognitive impairment by GABA_(A) receptor modulation. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one GABA_(A) receptormodulator as described supra and instructions (e.g., labeling)indicating the contained GABA_(A) receptor ligand is to be used fortreating a disorder responsive to GABA_(A) receptor modulation in thepatient.

[0260] In a separate aspect, the invention provides a method ofpotentiating the actions of other CNS active compounds, which comprisesadministering an effective amount of a compound of the invention incombination with another CNS active compound. Such CNS active compoundsinclude, but are not limited to the following: for anxiety, serotoninreceptor (e.g. 5-HT_(1A)) agonists and antagonists; for anxiety anddepression, neurokinin receptor antagonists or corticotropin releasingfactor receptor (CRF₁) antagonists; for sleep disorders, melatoninreceptor agonists; and for neurodegenerative disorders, such asAlzheimer's dementia, nicotinic agonists, muscarinic agents,acetylcholinesterase inhibitors and dopamine receptor agonists.Particularly the invention provides a method of potentiating theantidepressant activity of selective serotonin reuptake inhibitors(SSRIs) by administering an effective amount of a GABA agonist compoundof the invention in combination with an SSRI.

[0261] Combination administration can be carried out in a fashionanalogous to that disclosed in Da-Rocha, et. al., J. Psychopharmacology(1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10)1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132.Also see, the discussion of the use of the GABA_(A) receptor ligand3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinicagonists, muscarinic agonists, and acetylcholinesterase inhibitors, inPCT International publications Nos. WO 99/47142, WO 99/47171, and WO99/47131, respectively. Also see in this regard PCT Internationalpublication No. WO 99/37303 for its discussion of the use of a class ofGABA_(A) receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, incombination with SSRIs.

[0262] The present invention also pertains to methods of inhibiting thebinding of benzodiazepine compounds, such as Ro15-1788, to the GABA_(A)receptors which methods involve contacting a compound of the inventionwith cells expressing GABA_(A) receptors, wherein the compound ispresent at a concentration sufficient to inhibit benzodiazepine bindingto GABA_(A) receptors in vitro. This method includes inhibiting thebinding of benzodiazepine compounds to GABA_(A) receptors in vivo, e.g.,in a patient given an amount of a compound of Formula I that would besufficient to inhibit the binding of benzodiazepine compounds toGABA_(A) receptors in vitro. In one embodiment, such methods are usefulin treating benzodiazepine drug overdose. The amount of a compound thatwould be sufficient to inhibit the binding of a benzodiazepine compoundto the GABA_(A) receptor may be readily determined via an GABA_(A)receptor binding assay, such as the assay described in Example 50. TheGABA_(A) receptors used to determine in vitro binding may be obtainedfrom a variety of sources, for example from preparations of rat cortexor from cells expressing cloned human GABA_(A) receptors.

[0263] The present invention also pertains to methods for altering thesignal-transducing activity, particularly the chloride ion conductanceof GABA_(A) receptors, said method comprising exposing cells expressingsuch receptors to an effective amount of a compound of the invention.This method includes altering the signal-transducing activity ofGABA_(A) receptors in vivo, e.g., in a patient given an amount of acompound of Formula I that would be sufficient to alter thesignal-transducing activity of GABA_(A) receptors in vitro. The amountof a compound that would be sufficient to alter the signal-transducingactivity of GABA_(A) receptors may be determined via a GABA_(A) receptorsignal transduction assay, such as the assay described in Example 51.

[0264] The GABA_(A) receptor ligands provided by this invention andlabeled derivatives thereof are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to theGABA_(A) receptor.

[0265] Labeled derivatives the GABA_(A) receptor ligands provided bythis invention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

[0266] Definitions

[0267] If the compounds of the present invention have asymmetriccenters, then this invention includes all of the optical isomers andmixtures thereof.

[0268] In addition, compounds with carbon-carbon double bonds may occurin Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention.

[0269] Compounds of Formula I may contain one or more asymmetric carbonatoms, so that the compounds can exist in different stereoisomericforms. These compounds can be present as, for example, racemic mixtures,mixtures of diastereomers, and optically active forms including mixtureshaving one stereoisomer in enantiomeric excess and essentially purestereoisomers, i.e., individual stereoisomers. In these lattersituations, the single enantiomers can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

[0270] Representative compounds of the present invention, which areencompassed by Formula I, include, but are not limited to the compoundsin Table I and their pharmaceutically acceptable acid addition salts. Inaddition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

[0271] Non-toxic pharmaceutically acceptable salts include, but are notlimited to salts of inorganic acids such as hydrochloric, sulfuric,phosphoric, diphosphoric, hydrobromic, and nitric or salts of organicacids such as formic, citric, malonic, maleic, fumaric, tartaric,succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic,2-hydroxyethylsulfonic, salicylic and stearic. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. Thoseskilled in the art will recognize a wide variety of non-toxicpharmaceutically acceptable addition salts.

[0272] The present invention also encompasses the acylated prodrugs ofthe compounds of Formula I. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

[0273] When any variable (e.g. C₁-C₆ alkyl, C₁-C₈ alkyl, R₁—R₈, W, X,Ar, G or Q) occurs more than one time in any formula herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence.

[0274] As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. Where the number of carbon atoms in the alkyl group isunspecified, the group is a C₁-C₆ alkyl groups.

[0275] The term “alkoxy” represents an alkyl group of indicated numberof carbon atoms attached to the parent molecular moiety through anoxygen bridge. Examples of alkoxy groups include, for example, methoxy,ethoxy, propoxy and isopropoxy. Where the number of carbon atoms in thealkoxy group is unspecified the group is C₁-C₆ alkoxy.

[0276] The term “aryl” refers to an aromatic hydrocarbon ring systemcontaining at least one aromatic ring. The aromatic ring may optionallybe fused or otherwise attached to other aromatic hydrocarbon rings ornon-aromatic hydrocarbon rings. Examples of aryl groups include, forexample, phenyl, naphthyl, anthryl, phenanthryl,1,2,3,4-tetrahydronaphthyl and biphenyl. Preferred examples of arylgroups include phenyl and naphthyl.

[0277] The terms “halogen” or “halo” indicate fluorine, chlorine,bromine, and iodine. Preferred halo groups are fluoro, chloro, andbromo. Most preferred are fluoro and chloro.

[0278] The term “heterocycloalkyl” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heterocycloalkyl ring may be optionally fused to orotherwise attached to other heterocycloalkyl rings and/or non-aromatichydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, andpyrazole. Preferred heterocycloalkyl groups include piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-thiomorpholinyl, andpyrolidinyl.

[0279] The term “heteroaryl” refers to an aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heteroaryl ring may be fused or otherwise attached to one ormore heteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

[0280] The term “hydroxyalkyl” as used herein, refers to a hydroxygroup, attached to the parent molecular moiety through an alkyl group,as defined above.

[0281] As used herein, the term “oxo” refers to a doubly bonded oxygenatom forming carbonyl group with the carbon atom to which the oxygen isattached. Thus, where a ring contains one or more oxo groups, it isintended that that ring contains a carbonyl group in at least one of thering positions.

[0282] This invention relates to heterocyclic derivatives that bind tothe benzodiazepine site of GABA_(A) receptors, including human GABA_(A)receptors. A compound may bind to such sites with high affinity but nothigh specificity or a compound may bind with high selectivity but nothigh affinity.

[0283] The present invention also encompasses the prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies that may be employed to prepare non-toxicpharmaceutically acceptable prodrugs of the compounds encompassed byFormula I. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable solvates, such as water, ethanol,mineral oil, vegetable oil, and dimethylsulfoxide.

[0284] Pharmaceutical Preparations

[0285] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

[0286] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0287] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0288] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0289] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoringagents may be added to provide palatable oral preparations. Thesecompositions may be preserved by the addition of an anti-oxidant such asascorbic acid.

[0290] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents or suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0291] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil ora mineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0292] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0293] The compounds of general Formula I may also be administered inthe form of suppositories, e.g., for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

[0294] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0295] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

[0296] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0297] For administration to non-human animals, the composition may alsobe added to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

[0298] Representative illustrations of the preparation of compounds ofFormula 1 in the present invention are given in Schemes 1-3.

[0299] In Scheme I, W, X₁, X, and Y are as defined above for Formula 1and R is C₁-C₆alkyl, MeOH is methanol, EtOAc is ethyl acetate, DMF isN,N-dimethylformamide, POCl₃ is phosphorus oxychloride, and conc. isconcentrated. Heat, as used herein, means elevated temperature, such as,for example, about 40 to about 250° C.

[0300] In Scheme 2, X, X₁, Y, Z, W, W′, J, R₉ and R₁₀ are as definedabove for Formula 1, MeOH is methanol, BOP isbenzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate,TEA is triethylamine, DMF is N,N-dimethylformamide, THF istetrahydrofuran. Heat, as used herein, means elevated temperature, suchas, for example, about 40 to about 250° C.

[0301] In Scheme 3, X₁, Y, Z, W, X, n, R₁₁ and R₁₂ are as defined abovefor Formula 1, Me is methyl, Tol is toluene and heat as used herein,means elevated temperature, such as, for example, about 40 to about 250°C.

[0302] Those skilled in the art will recognize that it may be necessaryto utilize different solvents or reagents to achieve some of the abovetransformations.

[0303] The invention is illustrated further by the following examples,which are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them. Those having skillin the art will recognize that the starting materials may be varied andadditional steps employed to produce compounds encompassed by thepresent inventions, as demonstrated by the following examples. In somecases, protection of reactive functionalities may be necessary toachieve some of the above transformations. In general, such need forprotecting groups, as well as the conditions necessary to attach andremove such groups, will be apparent to those skilled in the art oforganic synthesis.

EXAMPLE 1

[0304] Preparation of1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]piperidine

[0305] (1) 4-[(Dimethylamino)methylene]-1H-2-benzopyran-1,3(4H)-dione

[0306] 100 ml of anhydrous DMF in a 1 liter round-bottomed, three neckedflask (fitted with a drying tube containing drierite, and a 125 mldropping funnel) is cooled in an ice-salt bath, and 31 ml of POCl₃ issubsequently added over a period of half an hour while stirring the DMF.The 125 ml dropping funnel is replaced with a 150 ml dropping funnel,and a solution of 54 g of homopthalic acid in 100 ml of DMF is added tothe flask over a period of one hour at <10° C. The reaction mixture isthen stirred at room temperature until a yellow paste was formed, andthen poured into ice water. The solid is collected by filtration, washedwith water and dried to give 54 g of the title compound as a yellowsolid, m.p. 137-40° C.

[0307] (2) Methyl 1H-2-benzopyran-1-oxo-4-carboxylate

[0308] Anhydrous HCl gas is continuously bubbled into a stirred solutionof the product from part 1 (54 g) in 500 ml of methanol at slowlyrefluxing temperature for 6 hours. The reaction mixture is concentratedunder vacuum. A NaHCO₃ solution is added to the residue. The solid wascollected by filtration, washed and dried to yield 29.4 g of the titlecompound as a solid, m.p. 88-90° C.

[0309] (3) Methyl 1,2-dihydro-1-oxo-4-isoquinolinecarboxylate

[0310] A mixture of the product from part 2 (29 g) and ammonium acetate(50 g) in 100 ml of acetic acid is stirred at 80° C. overnight, and thencooled and poured into water. The solid is collected by filtration,washed with water and dried to yield the title compound (25 g) as awhite solid, m.p. 258-60° C.

[0311] (4) Methyl 1-chloroisoquinoline-4-carboxylate

[0312] A mixture of the product from part 3 (12.5 g) in 50 ml of POCl₃is stirred at 100° C. for about two hours then cooled and concentratedunder vacuum. The residue is dissolved in 300 ml of CHCl₃, and theresulting solution is washed with aqueous NaHCO₃ and water, dried overNa₂SO₄, filtered and then concentrated to give the title compound, m.p.53-55° C.

[0313] (5) Methyl 1-isoquinolinecarbonitrile-4-carboxylate

[0314] A mixture of the product from part 4 (16 g) and potassium cyanide(5.4 g) in 50 ml of DMF was stirred at 90° C. for 4 hours. The mixtureis cooled and poured into water. The solid is then collected byfiltration, washed with water, and dried to give the title compound as atan solid (11 g), m.p. 91-94° C.

[0315] (6) Methyl 1-isoquinolinemethanamine-4-carboxylateDihydrochloride

[0316] A mixture of the product from part 5 (2 g) and 10% Pd on carbon(800 mg) in 50 ml of methanol containing 4 ml of conc. HCl ishydrogenated with a balloon of hydrogen for about half an hour. Themixture is filtered through celite and concentrated under vacuum to asolid. Recrystallization from EtOAc and methanol yields the titlecompound (1.8 g) as a white solid, m.p. 234-237° C. (dec).

[0317] (7) N-[(4-methoxycarbonylisoquinolin-1-yl)methyl]benzamide

[0318] Benzoyl chloride (0.78 ml) is added dropwise to a stirred mixtureof the product from part 6 (1.87 g) in 10 ml EtOAc and 10 ml ofsaturated aqueous NaHCO₃ solution. After stirring for 15 minutes, thelayers are separated, the organic layer is washed with water, dried,filtered and concentrated to a solid. The solid is washed with hexanesand dried to yield 1.97 g of the desired product as a white solid, m.p.140-142° C.

[0319] (8) Methyl 3-phenylimidazo[5,1-a]isoquinolin-6-carboxylate

[0320] A mixture of the product from part 7 (1.97 g) in 10 ml of POCl₃is stirred at 105° C. for two hours, then cooled and concentrated undervacuum. The residue is treated with EtOAc and washed with saturatedaqueous NaHCO₃ solution and water. The organic solution is dried overNa₂SO₄, filtered and then concentrated to afford a solid.Recrystallization from 2-propanol yields the title compound as a yellowsolid (0.7 g).

[0321] (9) 3-Phenylimidazo[5,1-a]isoquinolin-6-carboxylic Acid

[0322] A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in15 ml of methanol and 10 ml of water is stirred at 60° C. until asolution forms. The methanol is then evaporated in vacuo, and theremaining mixture is diluted with water. After adjusting the pH to 5-6with 1N HCl, the solid is collected by filtration, washed with water anddried to give the title compound (450 mg) as a yellow solid, m.p.187-90° C.

[0323] (10)1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-piperidine

[0324] A mixture of the product from part 9 (95 mg), BOP (220 mg),piperidine (56 mg) and TEA (67 mg) in 2 ml of DMF is stirred at roomtemperature for 18 hours. The mixture is added to aqueous NaHCO₃solution and extracted with EtOAc. The organic layer is washed withbrine and water, dried (Na₂SO₄), filtered and concentrated to afford afoam. Purification on a silica gel column, eluting with 5% methanol inmethylene chloride, gives the title compound. ¹H NMR (CDCl₃) δ 1.38-1.50and 1.60-1.80 (6H, m), 3.18-3.36 (2H, m), 3.65-3.95 (2H, m), 7.40-7.60(6H, m), 7.75 (2H, d), 7.95 (1H, s), 8.05 (1H, s), 8.10 (1H, d). Thehydrochloride salt was prepared by treating the free base in EtOAc witha solution of hydrogen chloride in ether and collecting by filtration.

[0325] LC-MS data: HPLC: 1.93 min (HPLC method: Zorbax XDB-C₁₈ column,4.6×30 mm, 3.5 μm particle size, 3 min gradient from 0 to 100% B with0.5 min hold at 100% B. Solvent A: 95% H₂O-5% MeOH-0.05% TFA; Solvent B:95% MeOH-5% H₂O-0.05% TFA). MS (ES⁺): m/e 356 [M+H]⁺.

EXAMPLES 2-40

[0326] The following compounds are prepared using procedures analogousto those of Example 1. The compounds of these examples have the generalstructure shown below:

[0327] where Q and W are defined in the following Table 1. LC-MS dataare given as HPLC retention times (rt) and [M+H]⁺. The HPLC retentiontimes of Table 1 are obtained by the method given in Example 1. TABLE 1HPLC Ex. rt No. Q W Compound Name (min) [M + H]⁺ 2

1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- pyrrolidine1.70 342 3

(R)-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-2-hydroxymethyl- pyrrolidine 1.47 372 4

4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- morpholine 1.44358 5

cis-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-2,6-dimethylpiperidine 2.27 384 6

4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- thiomorpholine1.84 374 7

1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-4-methylpiperazine 0.94 371 8

cis-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-3,5-dimethylpiperazine 1.13 385 9

1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-N,N-dimethylamine 1.40 316 10

1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-N,N-diethylamine 1.80 344 11

1-{[3-(4-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}pyrrolidine 1.80 360 12

(R)-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-2- hydroxymethyl- pyrrolidine 1.63 390 13

1-{[3-(4-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}piperidine 2.08 374 14

1-{[3-(2-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}pyrrolidine 1.97 360 15

(R)-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-2- hydroxymethyl- pyrrolidine 1.73 390 16

1-{[3-(2-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}piperidine 2.22 374 17

1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-pyrrolidine 1.61 348 18

(R)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2-hydroxymethyl- pyrrolidine 1.40 378 19

1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-piperidine 1.89 362 20

4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- 1,1-dioxido-thiomorpholine 1.24 406 21

cis-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3,5- dimethyl-piperazine 1.22 402 22

cis-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}}-3,5- dimethyl-piperazine 1.37 402 23

cis-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-}}-3,5- dimethyl-piperazine 1.04 391 24

1-{[3-(4-Chlorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}pyrrolidine 2.10 376 25

(R)-1-{[3-(4- Chlorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-2- hydroxymethyl- pyrrolidine 1.92 406 26

cis-1-{[3-(4- Chlorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3,5- dimethyl-piperazine 1.54 419 27

1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-4-methylpiperidine 376 28

(R)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3-methyl- piperazine 377 29

(S)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3-methyl- piperazine 377 30

4-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}morpholine364 31

1-{[3-(3-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}pyrrolidine 360 32

cis-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2,5-dimethylpiperazine 391 33

1-{[3-(4- Methylisoxazol-3-yl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}pyrrolidine 347 34

4-{[3-(3-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}morpholine 376 35

(R)-1-{[3-(3- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-2- hydroxymethyl- pyrrolidine 390 36

1-{[3-(3-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}piperidine 374 37

S-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-3-methylpiperazine 371 38

(S)-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3- methylpiperazine 389 39

(S)-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}-3- methylpiperazine 389 40

(S)-1-{[3-(4- Methoxyphenyl)- imidazo[5,1- a]isoquinolin-6-yl]carbonyl}- homopiperazine 400

EXAMPLE 41

[0328] Preparation of1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

[0329] (1) Methyl3-phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylate

[0330] A mixture of methyl 1-chloroisoquinoline-4-carboxylate, preparedessentially according to procedures described in Example 1, part 4, (293mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C.overnight. The mixture is cooled and poured into water. The solid isthen collected by filtration and dried to give the title compound as asolid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS(ES⁺) m/e 304 [M+H]⁺. (The HPLC retention time is obtained by the methodof Example 1).

[0331] (2) 3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylic Acid

[0332] This compound is prepared using the procedure described inExample 1, part 9 with the product of part 1 of this example being usedas the starting material.

[0333] (3)1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

[0334] This compound is prepared essentially using the proceduredescribed in Example 1, part 10 with the product of part 2 of thisexample being used as the starting material. Data for the titlecompound: ¹H NMR (CDCl3) δ 1.38-2.00 (6H, m), 3.16-3.36 (2H, m),3.65-3.95 (2H, m), 7.50-7.86 (8H, m), 8.05 (1H, s), 8.82 (1H, d).

[0335] LC-MS data: HPLC: 2.13 min. MS (ES⁺) m/e 357 [M+H]⁺. (The HPLCretention time is obtained by the method given in Example 1).

EXAMPLES 42-45

[0336] The following compounds are prepared by procedures analogous tothose of Example 41. These compounds are represented by the generalstructure shown below:

[0337] where Q and W are defined in Table 2. HPLC-MS data are given asHPLC retention times (Tr) and [M+H]⁺. The HPLC retention time isobtained by the method of Example 1. TABLE 2 HPLC Ex. (Tr) No. Q WCompound Name (min) [M + H]⁺ 42

1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6-yl)carbonyl]pyrrolidine 1.93 343 43

(R)-1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6- yl)carbonyl]-2-hydroxymethyl- pyrrolidine 1.73 373 44

4-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6-yl)carbonyl]morpholine 1.74 359 45

cis-1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6-yl)carbonyl]-3,5- dimethylpiperazine 1.37 386

EXAMPLE 46

[0338] Preparation of3-Phenyl-6-(S-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-yl-)-imidazo[5,1-a]isoquinoline

[0339] A solution of trimethylaluminum in anhydrous toluene (1M, 2.5 ml)is added dropwise to a stirred solution of S-2-(aminomethyl) pyrrolidine(250 mg) in 10 ml of anhydrous toluene. The mixture is then slowlywarmed to 80° C. and stirred for one hour. After cooling to roomtemperature, methyl 3-phenylimidazo [5,1-a] isoquinolin-6-carboxylate(prepared essentially according to procedures described in Example 1,part 8, 97 mg) was added in one portion. The reaction mixture is heatedat reflux for 12 hours under nitrogen. After cooling, the solution istreated dropwise with 5 ml of water, diluted with 10 ml of methanol and10 ml of methylene chloride, and refluxed for another 15 minutes. Afterfiltration over celite and Na₂SO₄, and solvent evaporation, the residueis mixed with EtOAc and water. The organic layer is then separated,washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The residue is purified on a silica gel column, eluting with 5% methanolin methylene chloride to yield the titled compound. ¹H NMR (CDCl₃) δ1.40-2.05 (4H, m), 3.00-3.20 (2H, m), 3.80-4.20 (3H, m), 7.40-7.62 (5H,m), 7.80 (2H, d), 7.95 (1H, s), 8.08 (1H, d), 8.35 (1H, d), 8.40 (1H,s).

[0340] LC-MS data: HPLC: 1.51 min. MS (ES⁺) m/e 353 [M+H]⁺. The HPLCretention time was obtained by the method of Example 1.

EXAMPLE 47

[0341] Preparation of1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

[0342] (1) 3-phenyl-1,2,4-Triazolo[3,4-a]phthalazine-6-carboxylic Acid

[0343] A mixture of 6-Chloro-3-phenyl-1,2,4-Triazolo[3,4-a] phthalazine(2.0 g, prepared according to procedures described in Zh. Org. Khim.(1975), 11(7), 1570-2 and J. Med. Chem. (1988), 31(6), 1115-23.) andcopper cynaide (2.0 g) in 50 ml of DMSO is stirred at 140° C. overnight.The mixture is cooled, poured into water and extracted with methylenechloride. The organic layer is washed with water, dried over Na₂SO₄ andconcentrated to give a tan solid which is then dissolved in 50 mL ofmethanol. The resulting solution is saturated with HCl gas and themixture is stirred at room temperature overnight. 20 mL of water and 1mL of 10 N NaOH solution are added, the resulting mixture is then heatedunder reflux for 4 hours. The methanol is then evaporated in vacuo, andthe remaining mixture is diluted with water. After adjusting the pH to4-5 with 1N HCl, the solid is collected by filtration, and dried to givethe title compound as a solid.

[0344] (2)1-[(3-Phenyl-1,2,4-triazolo[3,4-a]phthalazine-6-yl)carbonyl]piperidine

[0345] This compound is prepared essentially using the proceduredescribed in Example 1, part 10 with the product of part 1 of thisexample being used as the starting material.

EXAMPLE 48

[0346] Preparation of Radiolabeled Probe Compounds of the Invention

[0347] The compounds of the invention may be prepared as radiolabeledprobes by carrying out their synthesis using precursors comprising atleast one atom that is a radioisotope. The radioisotope is preferablyselected from of at least one of carbon (preferably ¹⁴C), hydrogen(preferably ³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I).Such radiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

[0348] Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Tritium labeled probecompounds can also be prepared, when appropriate, by sodium borotritidereduction. Such preparations are also conveniently carried out as acustom radiolabeling by any of the suppliers listed in the precedingparagraph using the compound of the invention as substrate.

EXAMPLE 49

[0349] Receptor Autoradiography

[0350] Receptor autoradiography (receptor mapping) is carried out invitro as described by Kuhar in sections 8.1.1 to 8.1.9 of CurrentProtocols in Pharmacology (1998) John Wiley & Sons, New York, usingradiolabeled compounds of the invention prepared as described in thepreceding Example.

EXAMPLE 50

[0351] Binding Assay

[0352] The high affinity and high selectivity of compounds of thisinvention for the benzodiazepine site of the GABA_(A) receptor isdemonstrated using the following binding assay. This assay is carriedout essentially as described by Thomas and Tallman (J. Bio. Chem. 1981;156:9838-9842, and J. Neurosci. 1983; 3:433-440).

[0353] Rat cortical tissue is dissected and homogenized in 25 volumes(w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissuehomogenate is centrifuged in the cold (4° C.) at 20,000×g for 20minutes. The supernatant is decanted, the pellet rehomogenized in thesame volume of buffer, and centrifuged again at 20,000×g. Thesupernatant of this centrifugation step is decanted and the pelletstored at −20° C. overnight. The pellet is then thawed and resuspendedin 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g andthe supernatant decanted. This wash step is repeated once. The pellet isfinally resuspended in 50 volumes of Buffer A.

[0354] Incubations contained 100 μl of tissue homogenate, 100 μl ofradioligand, (0.5 nM ³H-Ro15-1788 [³H-Flumazenil], specific activity 80Ci/mmol), and test compound or control (see below), and are brought to atotal volume of 500 μl with Buffer A. Incubations are carried for 30 minat 4° C. and then rapidly filtered through Whatman GFB filters toseparate free and bound ligand. Filters are washed twice with freshBuffer A and counted in a liquid scintillation counter. Nonspecificbinding (control) is determined by displacement of ³H Ro15-1788(³H-Flanazenil) with 10 μM Diazepam (Research BiochemicalsInternational, Natick, Mass.). Data are collected in triplicate,averaged, and percent inhibition of total specific binding (TotalSpecific Binding=Total−Nonspecific) is calculated for each compound.

[0355] A competition binding curve is obtained with up to 11 pointsspanning the compound concentration range from 10⁻¹² M to 10⁻⁵ Mobtained per curve by the method described above for determining percentinhibition. K_(i) values are calculated according the Cheng-Prussofequation. Each of the compounds shown and described in Examples 1through 46, and tested in this assay was found to have a K_(i) of <1 μM.

EXAMPLE 51

[0356] Electrophysiology

[0357] The following assay is used to determine if a compound of theinvention act as an agonist, an antagonist, or an inverse agonist at thebenzodiazepine site of the GABA_(A) receptor.

[0358] Assays are carried out as described in White and Gurley(NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling,and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications.Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.Xenopus Laevis oocytes are enzymatically isolated and injected withnon-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γsubunits, respectively. Of the nine combinations of α, β and γ subunitsdescribed in the White et al. publications, preferred combinations areα₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂. Preferably all of the subunit cRNAsin each combination are human clones or all are rat clones. The sequenceof each of these cloned subunits is available from GENBANK, e.g., humanα₁, GENBANK accession no. X14766, human α₂, GENBANK accession no.A28100; human α₃, GENBANK accession no. A28102; human α₅, GENBANKaccession no. A28104; human β₂, GENBANK accession no. M82919; human β₃,GENBANK accession no. Z20136; human γ₂, GENBANK accession no. X15376;rat 60 ₁, GENBANK accession no. L08490, rat α₂, GENBANK accession no.L08491; rat α₃, GENBANK accession no. L08492; rat α₅, GENBANK accessionno. L08494; rat β₂, GENBANK accession no. X15467; rat β₃, GENBANKaccession no. X15468; and rat γ₂, GENBANK accession no. L08497. For eachsubunit combination, sufficient message for each constituent subunit isinjected to provide current amplitudes of >10 nA when 1 μM GABA isapplied.

[0359] Compounds are evaluated against a GABA concentration that evokes<10% of the maximal evokable GABA current (e.g. 1 μM-9 μM). Each oocyteis exposed, to increasing concentrations of compound in order toevaluate a concentration/effect relationship. Compound efficacy iscalculated as a percent-change in current amplitude: 100*((Ic/I)−1),where Ic is the GABA evoked current amplitude observed in the presenceof test compound and I is the GABA evoked current amplitude observed inthe absence of the test compound.

[0360] Specificity of a compound for the benzodiazepine site isdetermined following completion of a concentration/effect curve. Afterwashing the oocyte sufficiently to remove previously applied compound,the oocyte is exposed to GABA+1 μM RO15-1788, followed by exposure toGABA+1 μM RO15-1788+test compound. Percent change due to addition ofcompound is calculated as described above. Any percent change observedin the presence of RO15-1788 is subtracted from the percent changes incurrent amplitude observed in the absence of 1 μM RO15-1788. These netvalues are used for the calculation of average efficacy and EC₅₀ valuesby standard methods. To evaluate average efficacy and EC₅₀ values, theconcentration/effect data are averaged across cells and fit to thelogistic equation.

[0361] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein: X represents Nor CR₁, wherein R₁ is hydrogen, halogen, hydroxy, cyano, nitro, amino,C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono ordi(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; X₁ represents N, CH, orC₁-C₆alkyl; Y and Z are independently hydrogen, halogen, hydroxy, cyano,nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; orY and Z together form an arylene ring or a C₃-C₈ cycloalkylene ring,each of which is optionally substituted with up to four groups R₂independently chosen at each occurrence from halogen, hydroxy, cyano,nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; Wis aryl or heteroaryl, each of which is optionally substituted with oneor more groups R_(A), wherein each R_(A) is independently i) halogen,hydroxy, cyano, nitro, amino, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂,—CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl),—S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), or —SO₂(C₁-C₈ alkyl); ii) aryl orheteroaryl, each of which is optionally substituted with one or twogroups independently selected from halogen, hydroxy, cyano, nitro,amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, monoor di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; iii) C₁-C₈alkyl,C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl(C₁-C₃alkyl), C₃-C₈cycloalkenyl, each of which is unsubstituted or substitutedby one or more substitutuents independently selected from hydroxy, oxo,halogen, C₁-C₆alkoxy, —CONH₂, —CONHC₁-C₆alkyl,—CON(C₁-C₆alkyl)(C₁-C₆alkyl), —COOH, and —CO₂C₁-C₆alkyl; or iv) NR₄R₅,wherein R₄, R₅ and the nitrogen to which they are attached form amonocyclic or bicyclic ring optionally containing one or more of oxo, O,S, SO, SO₂, or NR₆ wherein R₆ is hydrogen, C₁-C₆alkyl, orAr-(C₁-C₆alkyl) where Ar is aryl or heteroaryl, each of which isoptionally substituted with one or two groups independently selectedfrom halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino, andamino(C₁-C₆)alkyl; and Q is selected Formulas III, IV and V:

wherein: J is N or C₁-C₈ alkylene; and R₉ and R₁₀ are independentlyhydrogen, C₁-C₈ alkyl, or Ar₁, wherein Ar₁ is aryl or heteroaryl, eachof which may be substituted with one or two of R_(B), where each R_(B)independently carries the definition of R_(A); or R₉, R₁₀ and the atomto which they are attached form a 4- to 8-membered monocyclic orbicyclic ring optionally containing one or more double bonds or one ormore of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl,or Ar₁—(C₁-C₈ alkyl); wherein Ar₁ is optionally substituted with one ortwo of R_(B), where each R_(B) independently carries the definition ofR_(A); and wherein the monocyclic or bicyclic ring is optionallysubstituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ is selectedfrom the group consisting of hydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl,aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and R₁₂ is selected from thegroup consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ andR₁₂ together with the atoms to, which they are attached form a 5-8membered monocyclic ring which is optionally substituted with one ormore of halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino, oramino(C₁-C₆)alkyl; and n is 1, 2, 3, or 4; and W′ (i) independentlycarries the same definition as W; (ii) represents —OR where R is C₁-C₈alkyl or aryl(C₁-C₆)alkyl; or (iii) is M₅ where M₅ is hydroxy, C₁-C₈alkyl, aryl(C₁-C₆)alkyl or —N(C₁-C₄ alkyl)(C₁-C₄ alkoxy).
 2. A compoundaccording to claim 1 of the formula

wherein each R₂, Q, X, and X₁ are defined as in claim 1, and W isphenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl,benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl orbenzopyrazolyl, each of which is unsubstituted or substituted with oneor more substituents independently selected from the group consistingof: halogen, hydroxy, cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.3. A compound according to claim 2 wherein W is phenyl, naphthyl,thienyl, pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl,thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, eachof which is unsubstituted or substituted with one or more substituentsindependently selected from the group consisting of: halogen, hydroxy,cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂,—CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl),—S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 4. Acompound according to claim 3, wherein R₂ is independently selected ateach occurrence from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Q is selectedfrom the group consisting of Formulas III, IV and V:

wherein: J is N or C₁-C₈ alkylene; and R₉ and R₁₀ are independentlyhydrogen, C₁-C₈ alkyl; or R₉, R₁₀ and the atom to which they areattached form a 4- to 8-membered monocyclic or bicyclic ring, which maycontain one or more double bonds or one or more of oxo, O, S, SO, SO₂,or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic orbicyclic ring is optionally substituted with C₁-C₆ alkyl orhydroxy(C₁-C₆)alkyl; R₁₁ is selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, andaryl(C₁-C₆)alkanoyl; and R₁₂ is selected from the group consisting ofhydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ and R₁₂ together withthe atoms to which they are attached form a 5-8 membered monocyclicring, which is optionally substituted with C₁-C₆ alkyl; and n is 1, 2,3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl,isoxazolyl, or pyridyl, each of which is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl,trifluoromethoxy, and hydroxy.
 5. A compound according to claim 3,wherein X₁ is CR₁ and R₁ is hydrogen or C₁-C₆ alkyl.
 6. A compoundaccording to claim 5, wherein W is phenyl, naphthyl, thienyl, pyridyl,pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl, thiazolyl,benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: halogen, hydroxy, cyano, nitro,amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy,—SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl) —NH(C₁-C₈alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl),—N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 7. A compound according to claim6, wherein R₂ is independently selected at each occurrence from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl and trifluoromethoxy; Q is selected from the groupconsisting of Formulas III, IV and V wherein: J is N or C₁-C₈ alkylene;and R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or R₉, R₁₀ andthe atom to which they are attached form a 4- to 8-membered monocyclicor bicyclic ring, which may contain one or more double bonds or one ormore of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl;wherein the monocyclic or bicyclic ring is optionally substituted withC₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ is selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl,and aryl(C₁-C₆)alkanoyl; and R₁₂ is selected from the group consistingof hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ and R₁₂ together withthe atoms to which they are attached form a 5-8 membered monocyclicring, which is optionally substituted with C₁-C₆ alkyl; and n is 1, 2,3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl,isoxazolyl, or pyridyl, each of which is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl,trifluoromethoxy, and hydroxy.
 8. A compound according to claim 2,wherein X is CR₁ where R₁ is hydrogen or C₁-C₆ alkyl and X₁ is CH or acarbon atom substituted with C₁-C₆ alkyl.
 9. A compound according toclaim 3, wherein X is CR₁ where R₁ is hydrogen or C₁-C₆ alkyl and X₁ isCH or a carbon atom substituted with C₁-C₆ alkyl.
 10. A compoundaccording to claim 9, wherein R₂ is independently selected at eachoccurrence from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Q is selectedfrom the group consisting of Formulas III, IV and V wherein: J is N orC₁-C₈ alkylene; and R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl;or R₉, R₁₀ and the atom to which they are attached form a 4- to8-membered monocyclic or bicyclic ring, which may contain one or moredouble bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ ishydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ isselected from the group consisting of hydrogen, C₁-C₈ alkyl, C₁-C₈alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and R₁₂ is selectedfrom the group consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; orR₁₁ and R₁₂ together with the atoms to which they are attached form a5-8 membered monocyclic ring, which is optionally substituted with C₁-C₆alkyl; and n is 1, 2, 3, or 4; W′ phenyl, pyridyl, or naphthyl; and W isphenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstitutedor substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,trifluoromethyl, trifluoromethoxy, and hydroxy.
 11. A compound accordingto claim 1 of the formula

wherein R₂, Q, X, and X₁ are as defined in claim 1; p is 1, 2, 3, or 4;and W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxy, cyano, nitro, amino,C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, —SO₂NH₂,—SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl),—N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 12. A compound according to claim11 wherein p is 1, 2, or 3; and W is phenyl, naphthyl, thienyl, pyridyl,pyrazinyl, pyrimidyl, isoxazolyl, imidazolyl, furanyl, thiazolyl,benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: halogen, hydroxy, cyano, nitro,amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy,—SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl),—N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 13. A compound according to claim12, wherein R₂ is selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Qis selected from the group consisting of Formulas III, IV and V wherein:J is N or C₁-C₈ alkylene; and R₉ and R₁₀ are independently hydrogen,C₁-C₈ alkyl; or R₉, R₁₀ and the atom to which they are attached form a4- to 8-membered monocyclic or bicyclic ring, which may contain one ormore double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈ whereinR₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or bicyclic ring isoptionally substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ isselected from the group consisting of hydrogen, C₁-C₈ alkyl, C₁-C₈alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and R₁₂ is selectedfrom the group consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; orR₁₁ and R₁₂ together with the atoms to which they are attached form a5-8 membered monocyclic ring, which is optionally substituted withC₁-C₆alkyl; and n is 1, 2, 3, or 4; W′ phenyl, pyridyl, or naphthyl; andW is phenyl, thienyl, isoxazolyl, or pyridyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
 14. A compoundaccording to claim 11 wherein X₁ is CH.
 15. A compound according toclaim 12, wherein X₁ is CH.
 16. A compound according to claim 14,wherein X₁ is CH.
 17. A compound according to claim 1, wherein Y and Zare independently selected from hydrogen, halogen, hydroxy, cyano,nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl; and Wis phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxy, cyano, nitro, amino,C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, —SO₂NH₂,—SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl),—N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 18. A compound according to claim17, wherein: W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl,pyrimidyl, isoxazolyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl,pyrrolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: hydrogen, halogen, hydroxy, said C₁-C₈ alkyl,—O(C₁-C₈ alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁-C₈alkyl)(C₁-C₈ alkyl), amino, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁-C₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), andphenyl.
 19. A compound according to claim 18, wherein each R₂ isindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl or trifluoromethoxy; Q is selected from the groupconsisting of Formulas III, IV and V wherein: J is N or C₁-C₈ alkylene;and R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or R₉, R₁₀ andthe atom to which they are attached form a 4- to 8-membered monocyclicor bicyclic ring, which may contain one or more double bonds or one ormore of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl;wherein the monocyclic or bicyclic ring is optionally substituted withC₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ is selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl,and aryl(C₁-C₆)alkanoyl; and R₁₂ is selected from the group consistingof hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ and R₁₂ together withthe atoms to which they are attached form a 5-8 membered monocyclicring, which is optionally substituted with C₁-C₆alkyl; and n is 1, 2, 3,or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl,isoxazolyl, or pyridyl, each of which is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl,trifluoromethoxy, and hydroxy.
 20. A compound according to claim 17wherein X₁ and X are both CH.
 21. A compound according to claim 18,wherein X₁ and X are both CH.
 22. A compound according to claim 19,wherein X₁ and X are both CH.
 23. A compound according to claim 1, whichis: 1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]piperidine. 24.A compound according to claim 1, which is:1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]pyrrolidine.
 25. Acompound according to claim 1, which is:(R)-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2-hydroxymethyl-pyrrolidine26. A compound according to claim 1, which is:4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]morpholine.
 27. Acompound according to claim 1, which is:cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2,6-dimethylpiperidine.28. A compound according to claim 1, which is:4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-thiomorpholine. 29.A compound according to claim 1, which is:1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-4-methylpiperazine.30. A compound according to claim 1, which is:cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3,5-dimethylpiperazine.31. A compound according to claim 1, which is:1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-dimethylamine.32. A compound according to claim 1, which is:1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-diethylamine.33. A compound according to claim 1, which is:1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.34. A compound according to claim 1, which is:(R)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine.35. A compound according to claim 1, which is:1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine.36. A compound according to claim 1, which is:1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.37. A compound according to claim 1, which is:(R)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine.38. A compound according to claim 1, which is:1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine.39. A compound according to claim 1, which is:1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.40. A compound according to claim 1, which is:(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethylpyrrolidine.41. A compound according to claim 1, which is:1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine.42. A compound according to claim 1, which is:4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-1,1-dioxido-thiomorpholine.43. A compound according to claim 1, which is:cis-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3,5-dimethyl-piperazine.44. A compound according to claim 1, which is:cis-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}}-3,5-dimethyl-piperazine.45. A compound according to claim 1, which is:cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-}}-3,5-dimethyl-piperazine.46. A compound according to claim 1, which is:1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.47. A compound according to claim 1, which is:(R)-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine.48. A compound according to claim 1, which is:cis-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3,5-dimethyl-piperazine.49. A compound according to claim 1, which is:1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine.50. A compound according to claim 1, which is:(R)-1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]pyrrolidine.51. A compound according to claim 1, which is:R)-1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]-2-hydroxymethyl-pyrrolidine.52. A compound according to claim 1, which is:4-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]morpholine.53. A compound according to claim 1, which is:cis-1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]-3,5-dimethylpiperazine.54. A compound according to claim 1, which is:3-Phenyl-6-(S-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-yl-)-imidazo[5,1-a]isoquinoline.55. A compound according to claim 1, which is:1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-4-methylpiperidine.
 56. A compound according to claim 1, which is:(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methyl-piperazine.57. A compound according to claim 1, which is:(S-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methyl-piperazine.58. A compound according to claim 1, which is:4-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine.59. A compound according to claim 1, which is:1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.60. A compound according to claim 1, which is:cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2,5-dimethylpiperazine.61. A compound according to claim 1, which is:1-{[3-(4-Methylisoxazol-3-yl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.62. A compound according to claim 1, which is:4-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine.63. A compound according to claim 1, which is:(R)-1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine.64. A compound according to claim 1, which is:1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine.65. A compound according to claim 1, which is:(S)-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3-methylpiperazine.66. A compound according to claim 1, which is:S)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine.67. A compound according to claim 1, which is:(S)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine.68. A compound according to claim 1, which is:S-1-{[3-(4-Methoxyphenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-homopiperazine.69. A compound of the formula

wherein X₁ represents N, CH, or C₁-C₆alkyl; Y and Z are independentlyhydrogen, halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl,C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono ordi(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl, or Y and Z together form anarylene ring or a C₃-C₈ cycloalkylene ring, each of which is optionallysubstituted with up to four groups R₂ independently chosen at eachoccurrence from halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl,C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono ordi(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl; R is C₁-C₆alkyl; R_(N) ishydrogen, C₁-C₆ alkyl, or —C(O)W where W is aryl or heteroaryl, each ofwhich is optionally substituted with one or more groups R_(A), whereineach R_(A) is independently i) halogen, hydroxy, cyano, nitro, amino,C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈alkyl)(C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), or —SO₂(C₁-C₈ alkyl); ii) aryl or heteroaryl, each of which isoptionally substituted with one or two groups independently selectedfrom halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino, andamino(C₁-C₆)alkyl; iii) C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl,C₃-C₈cycloalkyl, C₃-C₈cycloalkyl(C₁-C₃ alkyl), C₃-C₈cycloalkenyl, eachof which is unsubstituted or substituted by one or more substitutuentsindependently selected from hydroxy, oxo, halogen, C₁-C₆alkoxy, —CONH₂,—CONHC₁-C₆alkyl, —CON(C₁-C₆alkyl)(C₁-C₆alkyl), —COOH, and—CO₂C₁-C₆alkyl; iv) NR₄R₅, wherein R₄ and R₅ and the nitrogen to whichthey are attached form a monocyclic or bicyclic ring that may containone or more of oxo, O, S, SO, SO₂, or NR₆ (wherein R₆ is hydrogen,C₁-C₆alkyl, or Ar-(C₁-C₆alkyl) where Ar is aryl or heteroaryl each ofwhich is optionally substituted with one or two groups independentlyselected from halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino,and amino(C₁-C₆)alkyl.
 70. A compound according to claim 69, which hasthe formula

wherein X₁, R, and each R₂ are as defined in claim 69, and R_(N) ishydrogen or —C(O)W.
 71. A compound according to claim 70, wherein R_(N)is hydrogen.
 72. A compound according to claim 70 wherein R_(N) is—C(O)W where W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl,pyrimidyl, isoxazolyl, imidazolyl, furanyl, thiazolyl benzothiazolyl,pyrrolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: hydrogen, halogen, hydroxy, said C₁-C₈ alkyl,—O(C₁-C₈ alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁-C₈alkyl)(C₁-C₈ alkyl), amino, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁-C₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), andphenyl.
 73. A compound according to claim 72 wherein each R₂ isindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,trifluoromethyl or trifluoromethoxy; W is phenyl, thienyl, or pyridyl,each of which is unsubstituted or substituted with one or more groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,trifluoromethyl, trifluoromethoxy, and hydroxy; and X₁ is N or CR₁;wherein R₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, or C₁-C₆ alkoxy.74. A compound according to claim 1, wherein X is CH and Q is —C(O)ORwhere R is C₁-C₆ alkyl.
 75. A compound according to claim 1, wherein X₁is CH and Q is —C(O)OR where R is C₁-C₆ alkyl.
 76. A compound accordingto claim 75, wherein X and X₁ are both CH.
 77. A compound according toclaim 74, wherein Y and Z together with the atoms to which they areattached form a benzo ring, the benzo ring being optionally substitutedwith one or two groups R₂; and W is phenyl, naphthyl, thienyl, pyridyl,pyrazinyl, pyrimidyl, isoxazolyl, imidazolyl, furanyl, thiazolyl,benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: hydrogen, halogen, hydroxy, saidC₁-C₈ alkyl, —O(C₁-C₈ alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁-C₈ alkyl)(C₁-C₈ alkyl), amino, —NH(C₁-C₈ alkyl), —N(C₁-C₈alkyl)(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl), and phenyl.
 78. A compound according to claim75, wherein Y and Z together with the atoms which they are attached forma benzo ring, the benzo ring being optionally substituted with one ortwo groups R₂; and W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl,pyrimidyl, imidazolyl, furanyl, thiazolyl, benzothiazolyl, pyrrolyl,pyrazolyl or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more of the substituents independently selectedfrom the group consisting of: hydrogen, halogen, hydroxy, said C₁-C₈alkyl, —O(C₁-C₈ alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁-C₈ alkyl)(C₁-C₈ alkyl), amino, —NH(C₁-C₈ alkyl), —N(C₁-C₈alkyl)(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl), and phenyl.
 79. A compound according to claim76, wherein Y and Z together with the atoms to which they are attachedform a benzo ring, the benzo ring being optionally substituted with oneor two groups R₂; and W is phenyl, naphthyl, thienyl, pyridyl,pyrazinyl, pyrimidyl, isoxazolyl, imidazolyl, furanyl, thiazolyl,benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: hydrogen, halogen, hydroxy, saidC₁-C₈ alkyl, —O(C₁-C₈ alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁-C₈ alkyl)(C₁-C₈ alkyl), amino, —NH(C₁-C₈ alkyl), —N(C₁-C₈alkyl)(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈alkyl)(C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈alkyl), —SO₂(C₁-C₈ alkyl), and phenyl.
 80. A compound according to claim77, wherein each R₂ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, trifluoromethyl or trifluoromethoxy; W is phenyl, thienyl, orpyridyl, each of which is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy,and hydroxy; and X₁ is N or CH.
 81. A compound according to claim 78,wherein each R₂ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, trifluoromethyl or trifluoromethoxy; W is phenyl, thienyl, orpyridyl, each of which is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy,and hydroxy; and X is N or CH.
 82. A compound according to claim 1,wherein Q is —C(O)M₅.
 83. A compound according to claim 1 of the formula

wherein W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each ofwhich is optionally substituted with one, two, or three of V₁, V₂ andV₃, where V₁, V₂, and V₃ independently represent halogen, hydroxy, C₁-C₆alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈alkyl)(C₁-C₈ alkyl); R₁ and R₂ independently represent hydrogen,halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl); X is nitrogen or CR₁₁₁, whereR₁₁₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂,—CN, amino, —NH(C₁-C₈ alkyl)or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl); and R₉ andR₁₀ are independently hydrogen or C₁-C₈ alkyl; or R₉ and R₁₀ togetherrepresent a C₄-C₆ straight chain alkylene group which together with thenitrogen atom to which R₉ and R₁₀ are attached form a 5- to 7-memberedring optionally containing one or two double bonds, O and/or N—R₈ whereR₈ is hydrogen, C₁-C₈ alkyl, or HAr-(C₁-C₈)alkyl, where HAr is phenyl,pyridinyl, or pyrimidinyl, each of which is optionally substituted withone or two halogen, hydroxy, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₈alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈alkyl).
 84. A compound according to claim 1 of the formula

wherein W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each ofwhich is optionally substituted with one, two, or three of V₁, V₂ andV₃, where V₁, V₂, and V₃ independently represent halogen, hydroxy, C₁-C₆alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈alkyl)(C₁-C₈ alkyl); R₁ and R₂ independently represent hydrogen,halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl); X is nitrogen or CR₁₁₁, whereR₁₁₁ is hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂,—CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl); and W′represents (i) phenyl optionally substituted with one, two, or three ofT₁, T₂ and T₃, where T₁, T₂, and T₃ independently represent halogen,hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl),or —N(C₁-C₈ alkyl)(C₁-C₈ alkyl); (ii) —OR where R is C₁-C₈ alkyl oraryl(C₁-C₆)alkyl; or (iii) M₅ where M₅ is hydroxy, C₁-C₈ alkyl,aryl(C₁-C₆)alkyl or —N(C₁-C₄ alkyl)(C₁-C₄ alkoxy).
 85. A compoundaccording to claim 84, wherein X is nitrogen.
 86. A compound accordingto claim 85, wherein X is nitrogen.
 87. A compound according to claim84, wherein X is CH or a carbon atom substituted with (C₁-C₆) alkyl. 88.A compound according to claim 84, wherein X is CH or a carbon atomsubstituted with (C₁-C₆) alkyl.
 89. A compound according to claim 1 foruse in therapeutic treatment of a disease or disorder associated withpathogenic agonism, inverse agonism or antagonism of the GABA_(A)receptor.
 90. A pharmaceutical composition comprising a compoundaccording to claim 1 combined with at least one pharmaceuticallyacceptable carrier or excipient.
 91. A method for the treatment of adisease or disorder associated with pathogenic agonism, inverse agonismor antagonism of the GABA_(A) receptor, said method comprisingadministering to a patient in need of such treatment or prevention aneffective amount of a compound of claim
 1. 92. A method according toclaim 91 wherein the disease or disorder associated with pathogenicagonism, inverse agonism or antagonism of the GABA_(A) receptor isanxiety, depression, a sleep disorder, or cognitive impairment.
 93. Theuse of a compound according to claim 1 for the manufacture of amedicament for the treatment of a disease or disorder associated withpathogenic agonism, inverse agonism or antagonism of the GABA_(A)receptor.
 94. The use of a compound according to claim 1 for themanufacture of a medicament for the treatment of anxiety, depression,sleep disorders, or cognitive impairment.
 95. A method for localizingGABA_(A) receptors in a tissue sample comprising: contacting with thesample a detectably-labeled compound of claim 1 under conditions thatpermit binding of the compound to GABA_(A) receptors, washing the sampleto remove unbound compound, and detecting the bound compound.
 96. Amethod of inhibiting the binding of a benzodiazepine compound to aGABA_(A) receptor, said method comprising contacting a compound of claim1 with cells expressing such a receptor in the presence of thebenzodiazepine, wherein the compound is present at a concentrationsufficient to inhibit the binding a benzodiazepine compound to aGABA_(A) receptor in vitro.
 97. A method for altering thesignal-transducing activity of GABA_(A) receptors, said methodcomprising exposing cells expressing such receptors to a compoundaccording to claim 1 at a concentration sufficient to inhibit RO15-1788binding to cells expressing a cloned human GABA_(A) receptor in vitro.98. A packaged pharmaceutical composition comprising the pharmaceuticalcomposition of claim 85 in a container and instructions for using thecomposition to treat a patient suffering from a disorder responsive toagonism, inverse agonism or antagonism of the GABA_(A) receptor.
 99. Thepackaged pharmaceutical composition of claim 98, wherein said patient issuffering from anxiety, depression, a sleep disorder, attention deficitdisorder, Alzheimer's dementia, or cognitive impairment.
 100. A compoundaccording to claim 1 wherein in a assay of GABA_(A) receptor binding thecompound exhibits an K_(i) of 1 micromolar or less.
 101. A compoundaccording to claim 1 wherein in a assay of GABA_(A) receptor binding thecompound exhibits an K_(i) of 100 nanomolar or less.
 102. A compoundaccording to claim 1 wherein in a assay of GABA_(A) receptor binding thecompound exhibits an K_(i) of 10 nanomolar or less.